Snake bite therapy

ABSTRACT

A method of reducing local hemorrhage and tissue necrosis resulting from the bite or sting of a venomous animal whereby an envenomated mammal is treated with a compound of the formula: ##STR1## or a corresponding disulfide wherein n is 1, 2 or 3; Z is O, S or NH; R is H, a straight or branched chain lower alkyl group of from 1 to 4 carbon atoms, hydroxy, a straight or branched chain lower alkoxy group of from 1 to 4 carbon atoms, fluoro, chloro, bromo, iodo or trifluoromethyl; or a pharmaceutically acceptable salt thereof.

This is a continuation of copending application Ser. No. 140,446, filedApr. 17, 1980, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of Invention

This invention relates to the treatment of local hemorrhage and tissuenecrosis resulting from snake bite by the administration ofα-mercapto-β-aryl acrylic acids and the corresponding disulfides as wellas their pharmaceutically acceptable salts.

2. Description of the Prior Art

Venomous bites and stings, particularly venomous snake bites, result intens of thousands of deaths each year worldwide primarily inunder-developed countries. In developed countries where access tomedical facilities and subsequent treatment with antivenom is readilyavailable, death resulting from snake envenomation is rare. Althoughantivenom therapy is largely successful in reducing the mortalityassociated with venomous snake bites, it is less effective in reducinglocal hemorrhage and tissue necrosis, prominent symptoms ofenvenomation. Frequently the local tissue necrosis subsequent to a snakebite may be so severe as to result in permanent disfigurement,impairment or, in extreme cases, loss of an affected extremity.

Venom of poisonous snakes, and other venomous animals, is comprisedlargely or completely of a complex enzymatic mixture. The hemorrhagicfactors of snake venom, those enzymes which are responsible forhemorrhagic activity, have been found to be metal dependent. Eliminationof Ca (II), Mg (II) and Zn (II) from these hemorrhagic factors byvarious metal chelators in vitro eliminates the hemorrhagic activity,Tu, A. T., Venoms:Chemistry and Molecular Biology, John Wiley & Sons,New York (1977). See also Bjarnason, J. B. and Tu. A. T., Biochemistry17 (16) 3395 (1978); Ownby, C. L. et al., J. Clin. Pharm., 15 419(1975); Friederick, C., and Tu., A. T., Biochem. Pharm. 20 1549 (1971).

Thus, a mixture of diethylenetriaminepentaacetic acid (DTPA) andprocaine when injected within 15 minutes of envenomation orethylenediaminetetraacetic acid (EDTA) when injected within 30 minutesof envenomation by snake in the vicinity of the bite is known to reducelocal hemorrhage; however, these agents are without effect in reducingtissue necrosis or lethality. Ownby, C. L., et. al., supra. Holvey, D.N., ed., The Merck Manual of Diagnosis and Therapy, 13th Edition, MerckSharp and Dohme Research Laboratories, Rahway, N.J., 1972, page 1987.Moreover, EDTA is contraindicated in the presence of a disturbedelectrolyte balance, a condition not uncommon with many snake bitevictims. At present no agent is known to be topically effective againstthe local hemorrhage and tissue necrosis caused by envenomation.

Mercapto acrylic acids and their disulfides are known to be potentinhibitors of various metal dependent enzymes. Wagner, J., et al., Can.J. Chem., 55, 4028 (1977). However, their utility as topically effectiveagents useful in reducing local hemorrhage and tissue necrosis resultingfrom snake envenomation, as described below, is quite unexpected.

The mercaptoacrylic acids and their corresponding disulfides areadditionally disclosed at Rovazzoni, C. et al, Ann. Chem. (Rome) 52,305-12 (1962), Chim. Abstr. 57:9833g; Haskel, et al, J. Med. Chem. 13,697 (1970); Halestrap. A., Biochem. J. 148(1), 85 (1975) as well as inU.S. Pat. Nos. 4,124,718; 4,130,653; 4,169,149; 4,210,664; 4,210,665;and 4,226,882.

BRIEF SUMMARY OF INVENTION

This invention relates to a method of reducing local hemorrhage andtissue necrosis resulting from the bite or sting of venomous animalswhich comprises administering to an envenomated mammal a compound ofstructure 1 as well as a corresponding disulfide: ##STR2## wherein Z is0, S or NH; R is H, methyl, ethyl, hydroxy, methoxy, ethoxy, fluoro,chloro, bromo, iodo, or trifluoromethyl; n is 1, 2 or 3; or apharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF INVENTION

It is apparent from the foregoing general Formula 1 that the compoundsemployed in the present invention are α-mercapto-β-furylacrylic acids,α-mercapto-β-thienylacrylic acids, α-mercapto-β-pyrrylacrylic acids aswell as the corresponding disulfides of general Formula 2 which areα,α'-dithiobis(β-furylacrylic acids), α,α'-dithiobis(β-thienyl acrylicacids), and α,α'-dithiobis(β-pyrrylacrylic acids) and thepharmaceutically acceptable salts thereof. ##STR3##

Pharmaceutically acceptable salts of the compounds of general Formula 1or their corresponding disulfides of general Formula 2 shall be taken tomean a non-toxic alkali metal such as sodium or potassium; alkalineearth metal such as calcium or magnesium; ammonium ion or organicammonium ion such as tetramethylammonium ion, carboxylic acid salt.

As used herein, the term a straight or branched chain lower alkyl groupof from 1 to 4 carbon atoms is taken to mean methyl, ethyl, n-propyl,isopropyl, n-butyl and isobutyl.

As used herein, the term a straight or branched chain lower alkoxy groupof from 1 to 4 carbon atoms is taken to mean methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy and isobutoxy.

The preferred compounds of this invention are those compounds of formula1 and their disulfides wherein R is H, methyl, ethyl, hydroxy, methoxy,ethoxy, fluoro, chloro, bromo, iodo or trifluoromethyl; Z is 0, S, orNH; n is 1; and their pharmaceutically acceptable salts.

Still more preferred compounds of this invention are those compounds offormula 1 and their disulfides wherein Z is 0, S, or NH and R is H.

The most preferred compounds of this invention areα-mercapto-β-(2-furyl)acrylic acid and α,α'-dithiobis[β-(2-furyl)acrylicacid].

As examples of compounds of general Formula 1 and the disulfides thereofthere may be mentioned the following:

α-mercapto-β-(2-furyl)acrylic acid;

α-mercapto-β-(5-trifluoromethyl-2-furyl)acrylic acid;

α-mercapto-β-(3-thienyl)acrylic acid;

α-mercapto-β-(2-pyrryl)acrylic acid;

α,α'-dithiobis[β-(2-furyl)acrylic acid]; and

α,α'-dithiobis[β-(2-thienyl)acrylic acid].

The compounds of this invention may be prepared according to the generalmethod described by Campaigne, E. and Cline, P. E., J. Org. Chem., 21,32 (1956) by condensing the corresponding carboxaldehyde of generalformula 3 with rhodanine of formula 4 and subsequently splitting theproducts (5) in alkaline medium, according to the general reactionscheme: ##STR4## wherein in general Formulas 1, 3, 4 and 5 n is 1, 2, or3; Z is 0, S or NH; and R is H, a straight or branched chain lower alkylgroup from 1 to 4 carbon atoms, hydroxy, a straight or branched chainlower alkoxy group of from 1 to 4 carbon atoms, fluoro, chloro, bromo,iodo, or trifluoromethyl.

Where the disulfides of general Formula 1 are desired, they may beprepared by the general methods described by Campaigne, E. and Cline, P.E., supra, by oxidation of the corresponding acrylic acid of Formula 1with iodine in alcohol or moist carbon tetrachloride or by oxidationwith an organic peroxide such as benzoyl peroxide in benzene.

The desired salts may be prepared in the usual manner by reactionbetween a compound of formula 1 or a disulfide thereof andpharmaceutically acceptable alkali metal, alkaline earth metal,transition metal, ammonium or organic ammonium basic salt, for example,an alkoxide such as sodium methoxide or sodium ethoxide; a phenoxidesuch as sodium phenoxide; a hydroxide such as sodium hydroxide,potassium hydroxide or ammonium hydroxide; or a carbonate such as sodiumcarbonate, potassium carbonate, zinc carbonate, magnesium carbonate orsodium hydrogen carbonate.

The compounds of general Formula 1 and the corresponding disulfideswherein n is 1, 2 or 3; Z is 0, S, or NH; and R is H, a straight orbranched chain lower alkyl group of from 1 to 4 carbon atoms, hydroxy, astraight or branched chain lower alkoxy group of from 1 to 4 carbonatoms, fluoro, chloro, bromo, iodo, or trifluoromethyl, are useful inreducing local hemorrhage and tissue necrosis resulting fromenvenomation of mammals by the bite or sting of venomous animals. Thecompounds of the invention also appear to inhibit other poisonousfactors of snake venom, particularly when administered parenterally. Thecompounds described herein are superior to other agents which are knownto inhibit the hemorrhagic factors of venom in that they are topicallyeffective. Accordingly, non-medically trained personnel could initiatetopical treatment of a venomous bite or sting immediately afterenvenomation.

As used herein the term mammals is taken to mean primates includinghumans, sheep, horses, bovine cows and bulls, pigs, dogs, cats, rats andmice.

The term venomous animals is taken to mean venomous snakes such as pitvipers including Agkistrodon spp., Bothrops spp., Crotalus spp.,Trimeresurus spp., Lachesis mutus, and Sistrurus spp. and vipersincluding Bitis spp., Causus spp., Cerastes spp., Echis carinatus,Pseudocerasters persicus and Vipera spp.; as well as spiders, gilamonsters, centipedes, maggots, marine animals and other venomous animalswhose bite or sting produces local hemorrhage and tissue necrosis.

The term venom is intended to encompass any poisonous substance which isparenterally transmitted, that is subcutaneously or intramuscularlytransmitted, by the bite or sting of a venomous animal into a mammal andwhich contains various toxins such as hemotoxins, hemagglutinins,neurotoxins, leukotoxins, and endotheliotoxins. For the purposes of thisinvention, the ill-effects of a venom must include local hemorrhage andtissue necrosis. Any mammal which has been injected with a venom by thebite or sting of a venomous animal is said to be an envenomated mammal.

The term antivenom is intended to encompass an antitoxin used in thetreatment of the poisonous effects resulting from the bite or sting of avenomous animal. Antivenom is generally produced by thehyperimmunization of horses and is commonly available in a lyophilizedstate. Administration of such antitoxin to an envenomated mammalrequires parenteral injection by highly skilled medical personnel unlikethe topical administration of the compounds of this invention.

In practicing the present invention the compounds of Formula 1 and theirdisulfides as well as the pharmaceutically acceptable salts thereof areadministered to an envenomated mammal either alone, in combination withone another, or in combination with other agents known to be useful insnake bite therapy such as "antivenom". The compounds of this inventioncan be administered either orally; parenterally, for example,subcutaneously or intravenously; or preferably topically.

The compounds of Formula 1 can be formulated for oral administration assolid or liquid unit dosage forms. The solid dosage forms can be, forexample, tablets, coated or uncoated; capsules, hard or soft; powders,granules; or pills. For solid administration the active ingredients canbe combined with carriers, for example, binders such as acacia, cornstarch, or gelatin; disintegrating agents such as corn starch, guar gum,potato starch, or alginic acid; lubricants such as stearic acid ormagnesium stearate and inert fillers such as lactose, sucrose or cornstarch. Liquid oral compositions can be, for example, dispersion,suspensions, elixirs, syrups, or simple solutions in aqueous vehicle.For liquid administration the active ingredient can be combined with asterile liquid, for example, an oil such as peanut oil, sesame oil,cottonseed oil, corn oil or olive oil; a fatty acid such as oleic acid,stearic acid or isostearic acid; a fatty acid ester such as ethyloleate, isopropyl myristate, fatty acid glycerides, or acetylated fattyacid glycerides; an alcohol such as ethanol, isopropanol, hexadecylalcohol, glycerol, or propylene glycol; a glycerol ketal such as2,2-dimethyl-1,3-dioxolane-4-methanol; an ether such aspoly(ethyleneglycol) 400; a petroleum hydrocarbon such as mineral oil orpetrolatum; water; or with mixtures thereof; with or without theaddition of a pharmaceutically suitable surfactant, suspending agent, oremulsifying agent such as pectin, carbomers, methyl cellulose,hydroxypropyl cellulose or carboxymethyl cellulose as well as buffersand preservatives. Oral compositions may also contain coloring andflavoring agents.

    ______________________________________                                        Ingredients of a Tablet Formulation                                                                  Per Tablet                                             ______________________________________                                        (a) α-Mercapto-β-(2-furyl)acrylic acid                                                      100 mg                                               (b) Cornstarch           15 mg                                                (c) Lactose              33.5 mg                                              (d) Magnesium stearate   1.5 mg                                               ______________________________________                                    

For parenteral administration the compounds can be administered asinjectable dosages of a solution or suspension of the compound in aphysiologically acceptable diluent with a pharmaceutical carrier whichcan be a sterile liquid such as water and oils with or without theaddition of a surfactant and other pharmaceutically acceptableadjuvants. Illustrative of oils which can be employed in thesepreparations are those of petroleum, animal, vegetable, or syntheticorigin, for example, peanut oil, sesame oil, soybean oil, and mineraloil. In general, water, saline, aqueous dextrose and related sugarsolutions, ethanol and glycols such as propylene glycol or polyethyleneglycol are preferred liquid carriers for injectable solutions.

    ______________________________________                                        Preparation of a Parenteral Formulation                                       ______________________________________                                        (a) α,α'-Dithiobis[β-(2-thienyl)acrylic                                               1.000   g                                            (b) Polyoxyethylene sorbitan mono oleate                                                               2.000   g                                            (c) Sodium chloride      .128    g                                            (d) Sterile Water for injection qs ad                                                                  20.000  ml                                           ______________________________________                                    

The compounds of Formula 1 can be formulated for topical administrationas for example, an ointment, cream, lotion, suspension, solution, gel,dusting powder, aerosol or spray. For administration as a powder theactive ingredient can be combined with a carrier such as corn starch,potato starch, lactose or sucrose. For administration as an ointment,cream, lotion, suspension, solution or gel the active ingredient can becombined with an oil such as peanut oil, sesame oil, cottonseed oil,corn oil, or olive oil; a fatty acid such as oleic acid, stearic acid,or isostearic acid; a fatty acid ester such as ethyl oleate, isopropylmyristate, fatty acid glycerides, or acetylated fatty acid glycerides;an alcohol such as ethanol, isopropanol, hexadecyl alcohol, glycerol, orpropylene glycol; a glycerol ketal such as2,2-dimethyl-1,3-dioxolane-4-methanol; an ether such aspoly(ethyleneglycol)400; a petroleum hydrocarbon such as mineral oil orpetrolatum; water; silicones such as methylphenylpolysiloxane; or withmixtures thereof; with or without the addition of a pharmaceuticallysuitable surfactant, suspending agent, or emulsifying agent such aspectin, carbomers, methyl cellulose, hydroxypropyl cellulose orcarboxymethyl cellulose as well as buffers and preservatives. Foradministration as an aerosol or spray the compounds of this inventioncan be combined with solvents, buffers, surfactants, perfumes,antimicrobial agents, antioxidants and propellants. Such compositionscan be applied by means of a propellant under pressure or can be appliedby means of a compressible plastic spray bottle, a nebulizer or anatomizer without the use of a gaseous propellant.

    ______________________________________                                        Preparation of a Topical Formulation                                          ______________________________________                                        (a) α-Mercapto-β-(2-thienyl)acrylic acid                                                   10 g                                                  (b) Ethanol             90 g                                                  ______________________________________                                    

The amount of compound administered will vary over a wide rangedepending upon the mammal to be treated and the severity of the localhemorrhage and tissue necrosis and can be any amount effective inreducing local hemorrhage and tissue necrosis in envenomated mammals. Alocal hemorrhage and tissue necrosis reducing amount can be from about10 mg/kg to 1000 mg/kg preferably from about 25 mg/kg to about 250 mg/kgof body weight of the mammal per day. For example, a unit dosage formmay suitably contain about 1 mg to 100 mg of active ingredient asrepresented by Formula 1 or a corresponding disulfide as well as a saltthereof.

The following specific examples further illustrate the preparation anduse of compounds employed in the instant invention.

EXAMPLE 1 α-Mercapto-β-(5-trifluoromethyl-2-furyl)acrylic acid

In a three necked flask, a mixture of 3.4 g of5-trifluoromethyl-2-furfural, 2.92 g of rhodanine and 5.16 g of drysodium acetate in 35 ml of glacial acetic acid is stirred and heated toreflux. After ten minutes a yellow precipitate forms and heating iscontinued for 2 hours. The reaction mixture is cooled, diluted with 30ml of water, and the yellow precipitate is filtered, washed with waterand dried. After chromatography over silica with dichloromethane aseluent, and recrystallization from dichloromethane and pentane, there isobtained 3.7 g (yield 63%) of yellow crystals of5-(5-trifluoromethyl-2-furylmethylene)rhodanine. M.P. 174° C. R_(f)=0.41 with 3% methanol/dichloromethane on silica gel

    ______________________________________                                        Microanalysis                                                                              C      H          N    S                                         ______________________________________                                        Calculated   38.71  1.44       5.01 22.96                                     Found        38.70  1.56       5.10 22.91                                     ______________________________________                                    

NMR spectrum in CDCl₃.

parts per million/tetramethyl silane.

6.8 multiplet (ring protons).

7.38 singlet (exocyclic methylene).

1.58 g of the above 5-(5-trifluoromethyl-2-furylmethylene)rhodanine, 23ml of 1 N sodium hydroxide solution and 25 ml of water are stirred undernitrogen at room temperature for 10 hours. After cooling with an icebath and acidification with concentrated hydrochloric acid to pH 1.5,the resulting slurry is filtered to yield a slightly brown precipitatewhich is washed with 50 ml of water by stirring at room temperatureunder nitrogen and filtered to yield 0.8 g of slightly brown crystals(yield 60%) of α-mercapto-β-(5-trifluoromethyl-2-furyl)acrylic acid.M.P. 158° C.

    ______________________________________                                        Microanalysis                                                                             C            H      S                                             ______________________________________                                        Calculated  40.34        2.11   13.46                                         Found       40.65        2.27   13.7                                          ______________________________________                                    

NMR in acetone (d 6).

parts per million/tetramethylsilane.

7.10 multiplet (ring protons).

7.6 singlet (exocyclic methylene).

EXAMPLE 2 α,α'-Dithiobis[β-(2-furyl)acrylic acid]

Iodine is added to a solution of 100 g of potassium iodide in 500 ml ofwater to saturation. This saturated solution is added dropwise to asolution of α-mercapto-β-(2-furyl)acrylic acid in 500 ml of acetonitrileand 30 ml of water until the color of iodine persists. The crude productwhich precipitates is recrystallized from methanol. M.P. 215° C.

EXAMPLE 3 α,α'-Dithiobis[β-(2-thienyl)acrylic acid]

Substituting α-mercapto-β-(2-thienyl)acrylic acid forα-mercapto-β-(2-furyl)acrylic acid in the procedure of Example 2 givesα,α'-dithiobis[β-(2-thienyl)acrylic acid].

EXAMPLE 4 Effects of Topically Applied α-Mercapto-β-aryl acrylic acidson Hemorrhage Caused by Snake Venoms

Mice (5 per group) were injected subcutaneously with different amountsof snake venoms. Immediately after the injection and 1, 2 and 3 hourslater, the mice were treated topically with ethanol (vehicle) or with 20micromols of test compound dissolved in ethanol. Four hours afterenvenomation the mice were killed and skinned. Hemorrhages on the undersurface of the skin and on the underlying musculature were scored on ascale of 0 to 4, according to their severity. Two observers, unaware ofthe treatments the animals had received, independently did the scoring;the two scores for each mouse were averaged.

    __________________________________________________________________________                Mean Hemorrhagic Scores                                                  Dose of   α-mercapto-β-                                                              α-mercapto-β-(2-                                                            α,α'-dithiobis[β-                 Venom     (2-furyl)acrylic                                                                      thienyl)acrylic                                                                        (2-furyl)acrylic                            Snake Venom                                                                          (ug) Vehicle                                                                            acid    acid     acid]                                       __________________________________________________________________________    Agkistrodon                                                                          135  3.5  1.5                                                          contortrix                                                                           45   1.9  0.6                                                          laticinictus                                                                         15   1.0  1.0                                                          Agkistrodon                                                                          45   2.5  1.1                                                          piscivorus                                                                           15   1.6  0                                                            leukostoma                                                                           5    0.9  0                                                            Agkistrodon                                                                          135  4.0  2.3                                                          piscivorus                                                                           45   2.7  0.8                                                                 15   1.0  0.3                                                          Crotalus                                                                             45   4.0  2.9                                                          adamanteus                                                                           15   3.0  1.3                                                                 5    1.6  0.2                                                          Crotalus                                                                             45   3.0  1.9                                                          atrox  15   2.0  0.6                                                                 5    1.3  0                                                            Crotalus                                                                             45   3.4  1.8                                                          atrox  15   1.9  0.5                                                                 5    1.6  0.5                                                          Crotalus                                                                             45   3.2  1.7                                                          atrox  15   2.2  0.4                                                                 5    0.8  0.2                                                          Crotalus                                                                             45   4.0  3.7                                                          cerastes                                                                             15   3.4  2.0                                                          cerastes                                                                             5    2.4  0.8                                                          Crotalus                                                                             45   3.4  1.8                                                          horridus                                                                             15   1.9  0.2                                                          horridus                                                                             5    1.1  0                                                            Crotalus                                                                             45   0.6  0.4                                                          scutulatus                                                                           15   0.2  0.4                                                          scutulatus                                                                           5    0    0.6                                                          Crotalus                                                                             45   3.9  1.9                                                          viridis                                                                              15   3.0  0.7                                                          helleri                                                                              5    2.0  0.6                                                          Crotalus                                                                             45   3.9  1.6                                                          viridis                                                                              15   2.6  1.4                                                          viridis                                                                              5    2.0  0.1                                                          Sistrurus                                                                            45   1.9  1.0                                                          miliarius                                                                            15   0.1  0.2                                                          barbouri                                                                             5    0.2  0                                                            Bothrops                                                                             25   3.8  1.0                                                          jararaca                                                                             15   2.4  0.6                                                                 5    1.6  0                                                            Bothrops                                                                             45   2.9  2.3                                                          jararaca                                                                             15   2.4  0.4                                                                 5    1.1  0                                                            Lachesis                                                                             50   2.7  1.8                                                          mutus  17   1.6  1.0                                                                 6    0.9  0.4                                                          Trimeresurus                                                                         45   2.3  1.2                                                          flavoviridis                                                                         15   2.1  0.1                                                                 5    1.0  0.1                                                          Bitis  15   3.3  2.0                                                          arietans                                                                             5    3.3  0.8                                                                 1.7  1.7  0                                                            Bitis  9    3.7          2.3      2.6                                         arietans                                                                             3    2.5          1.2      1.9                                                1    1.4          0.1      0.8                                         Echis  50   3.4  2.4                                                          carinatus                                                                            17   2.7  2.0                                                                 6    0.6  1.0                                                          Vipera 100  2.8  1.9                                                          russelli                                                                             33   1.6  1.1                                                                 11   0.6  0.9                                                          __________________________________________________________________________

EXAMPLE 5

Mice (5 per group) were injected subcutaneously with 5 μg of Bitisarietans venom. Immediately after injection and 1 hour later, the micewere treated topically with ethanol (control) or with 20 micromols ofα-mercapto-β-(2-furyl)acrylic acid dissolved in ethanol. Four hoursafter envenomation the mice were killed and skinned. Mean HemorrhagicScores were determined as in Example 4. The Score for the acrylic acidwas found to be 1.2 as compared with the control score of 3.1.

EXAMPLE 6

Mice (5 per group) were injected with different amounts of Bitisarietans venom. Immediately after the injection the mice were treatedorally with 50% propylene glycol (vehicle) or withα-mercapto-β-(2-furyl)acrylic acid (50 mg/kg) dissolved in 50% propyleneglycol. Mean Hemorrhagic Scores were determined as in Example 4.

    ______________________________________                                                   Mean Hemorrhagic Scores                                            Dose of                α-mercapto-β-                               Venom (ug)   Vehicle   (2-furyl)acrylic acid                                  ______________________________________                                        9            3.6       2.6                                                    3            2.2       1.0                                                    1            2.2       0.4                                                    ______________________________________                                    

I claim:
 1. A method of reducing local hemorrhage and tissue necrosis inmammals resulting from the bite or sting of a venomous snake whichcomprises administering to said mammal a local hemorrhage and tissuenecrosis reducing amount of a compound having the formula: ##STR5## or acorresponding disulfide of the formula: ##STR6## wherein Z is 0 and R isselected from the group consisting of H, methyl, ethyl, hydroxy,methoxy, ethoxy, fluoro, chloro, bromo, iodo and trifluoromethyl; or apharmaceutically acceptable salt thereof.
 2. A method of claim 1 whereinthe compound is administered topically.
 3. A method of claim 1 whereinthe local hemorrhage and tissue necrosis results from the bite of avenomous pit viper.
 4. A method of claim 1 wherein the mammal is ahuman.
 5. A method of claim 1 wherein the compound isα-mercapto-β-(2-furyl)acrylic acid or a pharmaceutically acceptable saltthereof.
 6. A method of claim 1 wherein the compound isα,α'-dithiobis[β-(2-furyl)acrylic acid] or a pharmaceutically acceptablesalt thereof.